title: Circadian genes differentially affect tolerance to ethanol in Drosophila.
abstract: BACKGROUND
  There is a strong relationship between circadian rhythms and ethanol (EtOH) responses. EtOH consumption has been shown to disrupt physiological and behavioral circadian rhythms in mammals (Alcohol Clin Exp Res 2005b, 29, 1550). The Drosophila central circadian pacemaker is composed of proteins encoded by the per, tim, cyc, and Clk genes. Using Drosophila mutant analysis, we asked whether these central components of the circadian clock make the equivalent contribution toward EtOH tolerance and whether rhythmicity itself is necessary for tolerance.
  
  
  METHODS
  We tested flies carrying mutations in core clock genes for the capacity to acquire EtOH tolerance. Tolerance was assayed by comparing the sedation curves of populations during their first and second sedation. Animals that had acquired tolerance sedated more slowly. Movement was also monitored as the flies breathe the EtOH vapor to determine if other facets of the EtOH response were affected by the mutations. Gas chromatography was used to measure internal EtOH concentration. Constant light was used to nongenetically destabilize the PER and TIM proteins.
  
  
  RESULTS
  A group of circadian mutations, all of which eliminate circadian rhythms, do not disrupt tolerance identically. Mutations in per, tim, and cyc completely block tolerance. However, a mutation in Clk does not interfere with tolerance. Constant light also disrupts the capacity to acquire tolerance. These lines did not differ in EtOH absorption.
  
  
  CONCLUSIONS
  Mutations affecting different parts of the intracellular circadian clock can block the capacity to acquire rapid EtOH tolerance. However, the role of circadian genes in EtOH tolerance is independent of their role in producing circadian rhythmicity. The interference in the capacity to acquire EtOH tolerance by some circadian mutations is not merely a downstream effect of a nonfunctional circadian clock; instead, these circadian genes play an independent role in EtOH tolerance.
authors.affiliation: The Waggoner Center for Alcohol and Addiction Research , Section of Neurobiology, The University of Texas at Austin, Austin, Texas.
authors.forename: Jascha B
authors.initials: JB
authors.lastname: Pohl
authors.forename: Alfredo
authors.initials: A
authors.lastname: Ghezzi
authors.forename: Linda K
authors.initials: LK
authors.lastname: Lew
authors.forename: Roseanna B
authors.initials: RB
authors.lastname: Robles
authors.forename: Lawrence
authors.initials: L
authors.lastname: Cormack
authors.forename: Nigel S
authors.initials: NS
authors.lastname: Atkinson
mesh_terms: D000818:Animals; D002492:Central Nervous System Depressants / Q000494:pharmacology*; D057906:Circadian Clocks / Q000235:genetics*; D002940:Circadian Rhythm; D004330:Drosophila / Q000187:drug effects* / Q000235:genetics; D004361:Drug Tolerance / Q000235:genetics*; D000431:Ethanol / Q000494:pharmacology*; D005260:Female; D009154:Mutation
chemical_list: D002492:Central Nervous System Depressants; D000431:Ethanol
keywords: Alcohol Tolerance; Circadian Rhythm; Drosophila; Mutation